Dopamine beta-hydroxylase (DbH) converts dopamine (DA) to norepinephrine (NE), and can be assayed in the plasma, where its activity is under genetic control by an oligogenic mechanism. While linkage studies based on phenotypic markers, and molecular association studies, suggest the structural gene DBH is a major quantitative trait locus regulating plasma DbH activity, this hypothesis has never been tested by molecular linkage analysis. There is evidence for at least one additional locus contributing to the regulation of plasma DbH activity, but the identity of this locus is unknown. Identifying the loci responsible for regulating plasma DbH is important for genetic research on schizophrenia (SCZ), because several lines of evidence suggest that differences in plasma DbH activity associate with differences in the phenotypic presentation of SCZ. In addition, abundant evidence suggests that alteration in DA- and NE-medicated neuro-transmission influence core phenotypes relevant to SCZ psychopathology, such as executive and working memory. We therefore hypothesize that DBH is a modifying gene in SCZ, that interacts with susceptibility loci to alter the symptoms and course of the illness. This application proposes 4 aims: (1) to conduct linkage analysis of plasma DbH activity in a set of SCZ pedigrees from which plasma samples are available;(2) to conduct follow-up association analysis of that linkage study to identify loci and specific variants responsible for regulating plasma DbH;(3) to conduct a linkage analysis of SCZ in a larger collection of SCZ families, conditional on genotypes at 2 SNPs at DBH already established to associate strongly with plasma DbH activity;and (4) to conduct association analyses in the probands of those families to test the hypothesis that DbH-regulating SNPs associate with altered symptomatic profiles and course of illness. The proposed work is significant for the public health because SCZ is a common disorder that usually disables people just as they enter adulthood, leading to huge costs in productivity, large burdens on healthcare and criminal-justice systems, and enormous human suffering by patients and their families. Identifying predictors of varying outcomes in SCZ would open new avenues for development of targeted interventions that could significantly ameliorate the impact of SCZ on individuals and society.